tbuckley/cabot-search huggingface dataset:
Excess ventilation and exertional dyspnoea in heart failure and pulmonary hypertension
Authors: J. Alberto Neder, Devin B. Phillips, Denis E. O'Donnell, Jerome A. Dempsey
Journal: European Respiratory Journal (2022)

Increased ventilation relative to metabolic demands, indicating alveolar hyperventilation and/or increased physiological dead space (excess ventilation), is a key cause of exertional dyspnoea. Excess ventilation has assumed a prominent role in the functional assessment of patients with heart failure (HF) with reduced (HFrEF) or preserved (HFpEF) ejection fraction, pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). We herein provide the key pieces of information to the caring physician to 1) gain unique insights into the seeds of patients' shortness of breath and 2) develop a rationale for therapeutically lessening excess ventilation to mitigate this distressing symptom. Reduced bulk oxygen transfer induced by cardiac output limitation and/or right ventricle-pulmonary arterial uncoupling increase neurochemical afferent stimulation and (largely chemo-) receptor sensitivity, leading to alveolar hyperventilation in HFrEF, PAH and small-vessel, distal CTEPH. As such, interventions geared to improve central haemodynamics and/or reduce chemosensitivity have been particularly effective in lessening their excess ventilation. In contrast, 1) high filling pressures in HFpEF and 2) impaired lung perfusion leading to ventilation/perfusion mismatch in proximal CTEPH conspire to increase physiological dead space. Accordingly, 1) decreasing pulmonary capillary pressures and 2) mechanically unclogging larger pulmonary vessels (pulmonary endarterectomy and balloon pulmonary angioplasty) have been associated with larger decrements in excess ventilation. Exercise training has a strong beneficial effect across diseases. Addressing some major unanswered questions on the link of excess ventilation with exertional dyspnoea under the modulating influence of pharmacological and nonpharmacological interventions might prove instrumental to alleviate the devastating consequences of these prevalent diseases.
A Shigella species variant is causally linked to intractable functional constipation
Authors: Xin Chen, Tian-Tian Qiu, Ye Wang, Li-Yang Xu, Jie Sun, Zhi-Hui Jiang, Wei Zhao, Tao Tao, Yu-Wei Zhou, Li-Sha Wei, Ye-Qiong Li, Yan-Yan Zheng, Guo-Hua Zhou, Hua-Qun Chen, Jian Zhang, Xiao-Bo Feng, Fang-Yu Wang, Ning Li, Xue-Na Zhang, Jun Jiang, Min-Sheng Zhu
Journal: Journal of Clinical Investigation (2022)

Intractable functional constipation (IFC) is the most severe form of constipation, but its etiology has long been unknown. We hypothesized that IFC is caused by refractory infection by a pathogenic bacterium. Here, we isolated from patients with IFC a Shigella species - peristaltic contraction-inhibiting bacterium (PIB) - that significantly inhibited peristaltic contraction of the colon by production of docosapentenoic acid (DPA). PIB colonized mice for at least 6 months. Oral administration of PIB was sufficient to induce constipation, which was reversed by PIB-specific phages. A mutated PIB with reduced DPA was incapable of inhibiting colonic function and inducing constipation, suggesting that DPA produced by PIB was the key mediator of the genesis of constipation. PIBs were detected in stools of 56% (38 of 68) of the IFC patients, but not in those of non-IFC or healthy individuals (0 of 180). DPA levels in stools were elevated in 44.12% (30 of 68) of the IFC patients but none of the healthy volunteers (0 of 97). Our results suggest that Shigella sp. PIB may be the critical causative pathogen for IFC, and detection of fecal PIB plus DPA may be a reliable method for IFC diagnosis and classification.
Bleeding Outcomes after Noncardiac Surgery — Are We POISEd to Do Better?
Authors: Jeffrey S. Berger
Journal: New England Journal of Medicine (2022)

The number of adults who undergo major noncardiac surgery is increasing worldwide,1 including older patients with more coexisting conditions and increased risks of bleeding and thrombotic events.2 Although perioperative bleeding is an important complication that leads to excess morbidity and mortality,3 few therapies have been studied to prevent it. Tranexamic acid is a lysine analogue that competes with lysine residues on fibrin for the binding of plasminogen, inhibiting the interaction of plasmin with fibrin and thereby preventing the dissolution of fibrin clot. Tranexamic acid has been shown to reduce the risk of death from bleeding in randomized trials involving patients . . .
Thromboembolic Risk in Patients With Pneumonia and New-Onset Atrial Fibrillation Not Receiving Anticoagulation Therapy
Authors: Mette Søgaard, Flemming Skjøth, Peter B. Nielsen, Jesper Smit, Michael Dalager-Pedersen, Torben B. Larsen, Gregory Y. H. Lip
Journal: JAMA Network Open (2022)

<h3>Importance</h3> New-onset atrial fibrillation (AF) is commonly reported in patients with severe infections. However, the absolute risk of thromboembolic events without anticoagulation remains unknown. <h3>Objective</h3> To investigate the thromboembolic risks associated with AF in patients with pneumonia, assess the risk of recurrent AF, and examine the association of initiation of anticoagulation therapy with new-onset AF. <h3>Design, Setting, and Participants</h3> This population-based cohort study used linked Danish nationwide registries. Participants included patients hospitalized with incident community-acquired pneumonia in Denmark from 1998 to 2018. Statistical analysis was performed from August 15, 2021, to March 12, 2022. <h3>Exposures</h3> New-onset AF. <h3>Main Outcomes and Measures</h3> Thromboembolic events, recurrent AF, and all-cause death. Estimated risks were calculated for thromboembolism without anticoagulation therapy, new hospital or outpatient clinic contact with AF, initiation of anticoagulation therapy, and all-cause death at 1 and 3 years of follow-up. Death was treated as a competing risk, and inverse probability of censoring weights was used to account for patient censoring if they initiated anticoagulation therapy conditioned on AF. <h3>Results</h3> Among 274 196 patients hospitalized for community-acquired pneumonia, 6553 patients (mean age [SD], 79.1 [11.0] years; 3405 women [52.0%]) developed new-onset AF. The 1-year risk of thromboembolism was 0.8% (95% CI, 0.8%-0.8%) in patients without AF vs 2.1% (95% CI, 1.8%-2.5%) in patients with new-onset AF without anticoagulation; this risk was 1.4% (95% CI, 1.0%-2.0%) among patients with AF with intermediate stroke risk and 2.8% (95% CI, 2.3%-3.4%) in patients with AF with high stroke risk. Three-year risks were 3.5% (95% CI, 2.8%-4.3%) among patients with intermediate stroke risk and 5.3% (95% CI, 4.4%-6.5%) among patients with high stroke risk. Among patients with new-onset AF, 32.9% (95% CI, 31.8%-34.1%) had a new hospital contact with AF, and 14.0% (95% CI, 13.2%-14.9%) initiated anticoagulation therapy during the 3 years after incident AF diagnosis. At 3 years, the all-cause mortality rate was 25.7% (95% CI, 25.6%-25.9%) in patients with pneumonia without AF vs 49.8% (95% CI, 48.6%-51.1%) in patients with new-onset AF. <h3>Conclusions and Relevance</h3> This cohort study found that new-onset AF after community-acquired pneumonia was associated with an increased risk of thromboembolism, which may warrant anticoagulation therapy. Approximately one-third of patients had a new hospital or outpatient clinic contact for AF during the 3-year follow-up, suggesting that AF triggered by acute infections is not a transient, self-terminating condition that reverses with resolution of the infection.
Allergen immunotherapy effectively reduces the risk of exacerbations and lower respiratory tract infections in both seasonal and perennial allergic asthma: a nationwide epidemiological study
Authors: Christian Woehlk, Anna Von Bülow, Muzhda Ghanizada, Marianne Baastrup Søndergaard, Susanne Hansen, Celeste Porsbjerg
Journal: European Respiratory Journal (2022)

Background Allergic asthma is associated with increased risk of respiratory tract infections and exacerbations. It remains unclear whether this susceptibility is conditioned by seasonal or by perennial allergy. Aim To investigate perennial allergy compared with seasonal allergy as a risk factor for lower respiratory tract infections and exacerbations in asthma and whether this risk can be reduced by allergen immunotherapy (AIT). Methodology This is a prospective register-based nationwide study of 18–44-year-olds treated with AIT during 1995–2014. Based on the type of AIT and use of anti-asthmatic drugs, patients were subdivided into two groups: perennial allergic asthma (PAA) versus seasonal allergic asthma (SAA). Data on antibiotics against lower respiratory tract infections (LRTI) and oral corticosteroids for exacerbations were analysed before starting AIT (baseline) and 3 years after completing AIT (follow-up). Results We identified 2688 patients with asthma treated with AIT, of whom 1249 had PAA and 1439 had SAA. At baseline, patients with SAA had more exacerbations (23.8% versus 16.5%, p≤0.001), but there were no differences in LRTI. During the 3-year follow-up, we observed a highly significant reduction of exacerbations with an average decrease of 57% in PAA and 74% in SAA. In addition, we observed a significant reduction of LRTI in both PAA and SAA: 17% and 20% decrease, respectively. Conclusion AIT effectively reduced the risk of exacerbations and lower respiratory tract infections in both seasonal and perennial allergic asthma. Perennial allergy is seemingly not a stronger risk factor for respiratory infections and exacerbations than seasonal allergy.
Durable and dynamic hTERT immune responses following vaccination with the long-peptide cancer vaccine UV1: long-term follow-up of three phase I clinical trials
Authors: Espen Basmo Ellingsen, Elin Aamdal, Tormod Guren, Wolfgang Lilleby, Paal F Brunsvig, Sara M Mangsbo, Steinar Aamdal, Eivind Hovig, Nadia Mensali, Gustav Gaudernack, Else Marit Inderberg
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Therapeutic cancer vaccines represent a promising approach to improve clinical outcomes with immune checkpoint inhibition. UV1 is a second generation telomerase-targeting therapeutic cancer vaccine being investigated across multiple indications. Although telomerase is a near-universal tumor target, different treatment combinations applied across indications may affect the induced immune response. Three phase I/IIa clinical trials covering malignant melanoma, non-small cell lung cancer, and prostate cancer have been completed, with patients in follow-up for up to 8 years. Methods 52 patients were enrolled across the three trials. UV1 was given as monotherapy in the lung cancer trial and concurrent with combined androgen blockade in the prostate cancer trial. In the melanoma study, patients initiated ipilimumab treatment 1 week after the first vaccine dose. Patients were followed for UV1-specific immune responses at frequent intervals during vaccination, and every 6 months for up to 8 years in a follow-up period. Phenotypic and functional characterizations were performed on patient-derived vaccine-specific T cell responses. Results In total, 78.4% of treated patients mounted a measurable vaccine-induced T cell response in blood. The immune responses in the malignant melanoma trial, where UV1 was combined with ipilimumab, occurred more rapidly and frequently than in the lung and prostate cancer trials. In several patients, immune responses peaked years after their last vaccination. An in-depth characterization of the immune responses revealed polyfunctional CD4+ T cells producing interferon-γ and tumor necrosis factor-α on interaction with their antigen. Conclusion Long-term immunomonitoring of patients showed highly dynamic and persistent telomerase peptide-specific immune responses lasting up to 7.5 years after the initial vaccination, suggesting a plausible functional role of these T cells in long-term survivors. The superior immune response kinetics observed in the melanoma study substantiate the rationale for future combinatorial treatment strategies with UV1 vaccination and checkpoint inhibition for rapid and frequent induction of anti-telomerase immune responses in patients with cancer.
Patient Factors and Pathology and Ultrasonography Findings Associated With Appendectomy—Reply
Authors: Sarah E. Monsell, Giana H. Davidson, David R. Flum
Journal: JAMA Surgery (2022)

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Final results of the DisCoVeRy trial of remdesivir for patients admitted to hospital with COVID-19
Authors: Florence Ader, Maude Bouscambert-Duchamp, Maya Hites, Nathan Peiffer-Smadja, France Mentré, Charles Burdet, Jérôme Aboab, Florence Ader, Hafid Ait-Oufella, Antoine Altdorfer, Claire Andrejak, Pascal Andreu, Laurent Argaud, Firouzé Bani-Sadr, Drifa Belhadi, Leila Belkhir, François Benezit, Marc Berna, Mathieu Blot, Elisabeth Botelho-Nevers, Lila Bouadma, Olivier Bouchaud, David Bougon, Kevin Bouiller, Fanny Bounes-Vardon, Maude Bouscambert-Duchamp, David Boutoille, Alexandre Boyer, Sandra Braz, Cédric Bruel, Charles Burdet, André Cabié, Emmanuel Canet, Charles Cazanave, Cyrille Chabartier, Catherine Chirouze, Raphaël Clere-Jehl, Dominique Costagliola, Sandrine Couffin-Cadièrgues, Johan Courjon, Flora Crockett, François Danion, Aline Dechanet, Agathe Delbove, Jean Dellamonica, Christelle Delmas, Alpha Diallo, Félix Djossou, Clément Dubost, Alexandre Duvignaud, Alexander Egle, Olivier Epaulard, Loïc Epelboin, Hélène Esperou, Murielle Fartoukh, Karine Faure, Emmanuel Faure, Joao-Miguel Ferreira Ribeiro, Tristan Ferry, Cécile Ficko, Samy Figueiredo, Claire Fougerou, Vincent Fraipont, Benjamin Gaborit, Rostane Gaci, Amandine Gagneux-Brunon, Sébastien Gallien, Denis Garot, Alexandre Gaymard, Guillaume Geri, Sébastien Gibot, François Goehringer, Marie Gousseff, Richard Greil, Didier Gruson, Jérémie Guedj, Yves Hansmann, Olivier Hinschberger, Maya Hites, Stéphane Jaureguiberry, Vanessa Jeanmichel, Michael Joannidis, Solen Kerneis, Antoine Kimmoun, Kada Klouche, Marie Lachâtre, Karine Lacombe, Fabrice Laine, Bernd Lamprecht, Jean-Philippe Lanoix, Odile Launay, Bruno Laviolle, Minh-Patrick Lê, Vincent Le Moing, Jérôme Le Pavec, Yves Le Tulzo, Paul Le Turnier, David Lebeaux, Benjamin Lefevre, Sylvie Leroy, François-Xavier Lescure, Henry Lessire, Benjamin Leveau, Bruno Lina, Paul Loubet, Alain Makinson, Denis Malvy, Charles-Hugo Marquette, Guillaume Martin-Blondel, Martin Martinot, Julien Mayaux, Armand Mekontso-Dessap, France Mentré, Noémie Mercier, Ferhat Meziani, Jean-Paul Mira, Jean-Michel Molina, Xavier Monnet, Joy Mootien, Bruno Mourvillier, Bruno Mourvilliers, Marlène Murris-Espin, Jean-Christophe Navellou, Marion Noret, Saad Nseir, Walid Oulehri, José-Artur Paiva, Nathan Peiffer-Smadja, Thomas Perpoint, Gilles Peytavin, Gilles Pialoux, Benoît Pilmis, Vincent Piriou, Lionel Piroth, Julien Poissy, Valérie Pourcher, Jean-Pierre Quenot, François Raffi, Jean Reignier, Jean Reuter, Matthieu Revest, Jean-Christophe Richard, Béatrice Riu-Poulenc, Céline Robert, Pierre-Alexandre Roger, Claire Roger, Roberto Roncon-Albuquerque, Elisabeth Rouveix-Nordon, Yvon Ruch, Nadia Saidani, Juliette Saillard, Naomi Sayre, Eric Senneville, Albert Sotto, Thérèse Staub, Francois Stefan, Charles Tacquard, Nicolas Terzi, Julien Textoris, Guillaume Thiery, Jean-François Timsit, Violaine Tolsma, Sarah Tubiana, Jean-Marie Turmel, Florent Valour, Fanny Vardon-Bounes, Priyanka Velou, Gil Verschelden, Florent Wallet, Guilhem Wattecamps, Yazdan Yazdanpanah, Yoann Zerbib
Journal: The Lancet Infectious Diseases (2022)
Patient-Derived Organoid Pharmacotyping Guides Precision Medicine for Pancreatic Cancer
Authors: Yuqing Zhang, Courtney W. Houchen, Min Li
Journal: Clinical Cancer Research (2022)

Summary The patient-derived organoids (PDO) platform recapitulates the phenotype, genotype, and molecular characteristics of primary tumors. High-throughput drug screening in terms of pharmacotyping using standard-of-care chemotherapy agents in the PDO platform has shown promising sensitivities to guide precision medicine for individual patients with pancreatic ductal adenocarcinoma (PDAC) within a clinically relevant time frame. See related article by Seppälä et al., p. 3296
Effectiveness of Homologous and Heterologous Covid-19 Boosters against Omicron
Authors: Emma K Accorsi, Amadea Britton, Nong Shang, Katherine E Fleming-Dutra, Ruth Link-Gelles, Zachary R Smith, Gordana Derado, Joseph Miller, Stephanie J Schrag, Jennifer R Verani
Journal: New England Journal of Medicine (2022)

Effectiveness of Homologous and Heterologous Covid-19 Boosters against OmicronTo the Editor: For persons who received a single dose of the Ad26.COV2.S vaccine (Johnson & Johnson-Janssen) against coronavirus disease 2019 (Covid-19), a booster dose of a messenger RNA (mRNA) vaccine at least 2 months after the primary dose is recommended.Recipients of Ad26.COV2.S for both the primary and booster doses may receive a second booster dose of an mRNA Covid-19 vaccine at least 4 months after the first Ad26.COV2.S booster dose. 1 Immunogenicity data from a phase 1-2 clinical trial conducted before B.1.1.529and the BA sublineages of omicron emerged showed that increases in the titers of binding and neutralizing antibodies with heterologous boosting were similar to or greater than the increases with homologous boosting. 2In a study involving U.S. veterans, data that were obtained during a period in which omicron was the predominant circulating variant also showed that among Ad26.COV2.S recipients, vaccine effectiveness against omicron infection was higher with heterologous boosting than with homologous boosting 3 ; however, data from the general adult population and on vaccine effectiveness over time are lacking.More than 18 million doses of the Ad26.COV2.S vaccine have been administered in the United States alone 4 ; therefore, data are needed on boosting strategies that are effective over time.We performed a test-negative, case-control analysis to assess the effectiveness of four vaccination regimens against symptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during a period when omicron was the predominant circulating variant: a single priming dose of Ad26.COV2.S, a single priming dose of Ad26.COV2.S plus a booster dose of Ad26.COV2.S (Ad26.COV2.S/Ad26.COV2.S), a single priming dose of Ad26.COV2.
Fractal dimension of the brain in neurodegenerative disease and dementia: A systematic review
Authors: Elina T. Ziukelis, Elijah Mak, Maria-Eleni Dounavi, Li Su, John T O'Brien
Journal: Ageing Research Reviews (2022)

Sensitive and specific antemortem biomarkers of neurodegenerative disease and dementia are crucial to the pursuit of effective treatments, required both to reliably identify disease and to track its progression. Atrophy is the structural magnetic resonance imaging (MRI) hallmark of neurodegeneration. However in most cases it likely indicates a relatively advanced stage of disease less susceptible to treatment as some disease processes begin decades prior to clinical onset. Among emerging metrics that characterise brain shape rather than volume, fractal dimension (FD) quantifies shape complexity. FD has been applied in diverse fields of science to measure subtle changes in elaborate structures. We review its application thus far to structural MRI of the brain in neurodegenerative disease and dementia. We identified studies involving subjects who met criteria for mild cognitive impairment, Alzheimer's Disease, Vascular Dementia, Lewy Body Dementia, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, Parkinson's Disease, Huntington's Disease, Multiple Systems Atrophy, Spinocerebellar Ataxia and Multiple Sclerosis. The early literature suggests that neurodegenerative disease processes are usually associated with a decline in FD of the brain. The literature includes examples of disease-related change in FD occurring independently of atrophy, which if substantiated would represent a valuable advantage over other structural imaging metrics. However, it is likely to be non-specific and to exhibit complex spatial and temporal patterns. A more harmonious methodological approach across a larger number of studies as well as careful attention to technical factors associated with image processing and FD measurement will help to better elucidate the metric's utility.
Appropriate Antibiotic Prescribing—The Safer and Less Expensive Choice
Authors: Michael J. Smith, Bethany A. Wattles
Journal: JAMA Network Open (2022)

Anne M. Butler, PhD; Derek S. Brown, PhD; Michael J. Durkin, MD, MPH; John M. Sahrmann, MA; Katelin B. Nickel, MPH; Caroline A. O'Neil, MA, MPH; Margaret A. Olsen, PhD, MPH; David Y. Hyun, MD; Rachel M. Zetts, MPH; Jason G. Newland, MD, MEd
Empagliflozin in Heart Failure with a Preserved Ejection Fraction
Authors: Hiddo J L Heerspink, Lesley Inker, Tom Greene
Journal: New England Journal of Medicine (2022)

Empagliflozin in Heart Failure with a Preserved Ejection FractionTo the Editor: Anker et al. (Oct.14 issue) 1 report that in EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction), empagliflozin reduced the incidence of primary outcome events among patients with heart failure and a preserved ejection fraction, and they contrast their results with those with spironolactone in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial. 2 However, the incidences of cardiovascular death, death from any cause, and hospitalization for heart failure were higher in the empagliflozin group of EMPEROR-Preserved than in the spironolactone group of the TOPCAT trial.Although 82% of the patients were receiving diuretics at randomization in the TOPCAT trial, data on the use of diuretics were not shown in EMPEROR-Preserved. 1 A low overall use of diuretics in EMPEROR-Preserved would have created a bias in favor of empagliflozin, which acts as an osmotic diuretic.Concomitantly, the possible lack of an adequately dosed loop diuretic could have contributed to a higher overall mortality in EMPEROR-Preserved than in the TOPCAT trial.Can the authors provide data on the baseline diuretic use and comment on the apparently in-